Our understanding of the viral suppression and immune restoration following antiretroviral therapy of HIV infected individuals stems mainly from the virologic and immunologic assessment of their peripheral blood samples. However, peripheral blood represents only 2 percent of the total lymphocytes in the body. The remaining lymphocytes reside in the lymphoid organs. The gut-associated lymphoid tissue (GALT) harbors the majority of lymphoid tissue in the body. Therefore, suppression of viral replication and eradication of infected cells in gut lymphoid tissue may be important in containment of HIV-1 infection during highly active anti-retroviral therapy (HAART). However, our knowledge of intestinal mucosal immune responses and viral kinetics in HIV-1 infection is limited. The overall objective of this research proposal is to examine the effects of HAART on the virologic and immunologic outcome in GALT in comparison to peripheral blood in HIV-1 infected patients and to investigate the gender differences in the clinical outcome. We will test the hypothesis that suppression of viral loads and diversity, as well as the repopulation of CD4+ T cells in the gut lymphoid tissue will be important predictors of efficacy of HAART and that molecular correlates of protective mucosal immunity and containment of viral infection in gut lymphoid tissue can be identified. Longitudinal, small intestinal biopsy and peripheral blood samples will be obtained from HIV-1 infected men and women prior to and following HAART. Samples will also be obtained from long-term HIV-infected non-progressors and uninfected healthy controls. Viral suppression and evolution of viral variants will be examined in both the productively infected cell population in intestinal tissue and the latently-infected resting CD4+ T cells isolated from peripheral blood. The quantitative, as well as qualitative extent of CD4+ T cell repopulation will be determined. Mucosal immunity will be examined by measuring virus-specific cytotoxic T cell (CTL) responses. DNA Microarray based analysis of gene expression profiles in gut lymphoid tissue will be performed to identify molecular correlates of better clinical outcome. There are 3 specific aims. (1) To determine the effects of HAART on HIV-1 replication and evolution of viral variants in gut lymphoid tissue of HIV-infected men and women. (2) To determine the effects of HAART on the CD4+ T cell repopulation and HIV-1 specific cytotoxic T cell responses in gut lymphoid tissue of HIV-1 infected patients. (3) To determine the alterations in the host gene expression profiles in intestinal mucosa following HAART to determine pathogenic mechanisms and to identify molecular correlates of clinical outcome.